Kaiser Study Finds Link between First-line Tenofovir (Viread) Use and Kidney Impairment

		SUMMARY: Tenofovir (Viread, also in the Truvada and Atripla combination pills) can cause kidney (renal) impairment with long-term use, especially in patients with decreased kidney function at baseline, according to a study reported in the January 2010 Journal of Acquired Immune Deficiency Syndromes. These findings underline the importance of monitoring kidney function before and during treatment.

By Liz Highleyman

People with HIV have been shown to have higher rates of kidney disease. In some cases, this is related to HIV infection itself (HIV-associated nephropathy), but antiretroviral drugs may also play a role.

The nucleotide reverse transcriptase inhibitor tenofovir is eliminated by the kidneys and may accumulate in the proximal tubules, which maintain metabolic balance (e.g., stable pH) as the kidneys filter the blood.

In the pivotal clinical trial that led to its approval, tenofovir was not associated with kidney problems, but those studies excluded people with pre-existing kidney disease. Studies of "real world" populations have yielded conflicting data, with some showing no association and others showing increased risk in susceptible individuals.

To shed further light on this issue, Michael Horberg from Kaiser Permanente in Oakland, CA, and colleagues designed a study to characterize the long-term effects of tenofovir on kidney function in a large managed care organization.

This retrospective cohort analysis looked at medical records from treatment-naive HIV positive Kaiser Permanente members who started antiretroviral therapy during 2002-2005. The study compared 964 patients who started regimens containing tenofovir and 683 who started tenofovir-sparing regimens.

Baseline characteristics were similar overall, though tenofovir recipients were more likely to have hepatitis B coinfection (tenofovir is active against hepatitis B virus as well as HIV). Very few patients used the older protease inhibitor indinavir (Crixivan), which has also been linked to kidney dysfunction.

The researchers evaluated multiple measures of kidney function, including glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation, serum creatinine level, and development of renal proximal tubular dysfunction over a 2-year period.

They used multivariate models to adjust for confounding factors including age, sex, race (blacks are known to have a higher risk for HIV-associated nephropathy), history of diabetes, hypertension (high blood pressure), malignancy, hepatitis, concurrent medications, and baseline laboratory values including CD4 cell count.

Results

	Overall, 5% of patients taking tenofovir experienced a GFR decline of 50% or more, compared with 3% of patients on tenofovir-sparing regimens (P = 0.03).
	Patients taking tenofovir had a significantly larger relative decline in GFR through 104 weeks than those on tenofovir-sparing regimens (-7.6 mL/min/1.73 m(2); P < 0.001).
	However, the degree of difference varied according to baseline GFR, with the greatest effect seen in patients with initial GFR > 80 mL/min/1.73 m(2).
	Tenofovir recipients had significantly higher serum creatinine levels at 52 and 104 weeks (both P < 0.001).
	After controlling for other factors, tenofovir recipients were significantly more likely to develop proximal tubular dysfunction over time:
	Adjusted hazard ratio (HR) 1.95, or about twice the risk, at 52 weeks (P = 0.01); Adjusted HR 5.23, or more than 5-fold higher risk, at 104 weeks (P = 0.0004).
	Patients taking tenofovir also had a greater risk of drug discontinuation (adjusted HR 1.21; P = 0.02), especially as kidney function worsened.
	HIV suppression and changes in CD4 count were similar between the 2 groups.

Based on these findings, the study authors concluded, "Tenofovir is associated with greater effect on decline in renal function and a higher risk of proximal tubular dysfunction in antiretroviral naive patients initiating antiretroviral therapy."

"Given the current commitment to long-term, even life-long antiretroviral therapy, incremental small annual declines in kidney function could eventually lead to kidney failure and increased mortality," they continued in their discussion.

"We conclude that although efficacious, the potential long-term adverse effects on kidney function may limit the use of tenofovir for patients at high risk of renal complications," they summarized. "Long-term monitoring of renal function and the components of proximal tubular dysfunction in patients taking tenofovir should be considered."

HIV Initiative, Kaiser Permanente, Oakland, CA.

2/9/10

Reference
M Horberg, B Tang, W Towner, and others. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients. Journal of Acquired Immune Deficiency Syndromes 53(1): 62-69 (Abstract). January 2010.